ADHD has been consistently implicated in the development of substance problems (SP) related to adolescent misuse of nicotine, alcohol, and marijuana, but it remains uncertain to what degree this association reflects a specific causal effect of ADHD or a general contribution of comorbid childhood disruptive disorders. Gender and ADHD subtype effects have been understudied as they relate to the link between ADHD and SP, and longitudinal investigations that examine underlying mechanisms indicating how ADHD leads to the development of SP are also needed. The present data analysis proposal addresses these important public health questions by combining data from three community- based family studies focused on the prospective development of substance use disorders in adolescent twins. The recruited sample of 1881 same-sex adolescent pairs has undergone in-person comprehensive assessments of common childhood and adult mental health disorders and associated risk factors relevant to the development of SP from ages 11 to 17. The combined sample contains a substantial number of ADHD cases (N=533), including 205 girls, many with the less often studied inattentive subtype, allowing us to evaluate effects of both gender and ADHD subtype in each of three specific aims. Aim 1 examines general and specific pathways underlying the association between ADHD, its dimensional subtypes, and SP. In addition to employing biometric modeling to evaluate the genetic and environmental contributions to the observed relationships, we take advantage of the within-pair discordance in ADHD symptomatology to apply a novel co-twin control difference design to examine whether the association between ADHD and age-17 SP reflects the causal impact of ADHD on SP or the impact of genetic and environmental influences affecting both. We hypothesize that inattention constitutes a specifically salient risk factor for nicotine dependence in girls, one that may also figure importantly in their use of cannabis. Aim 2 considers the hypothesis that social and academic impairment together with internalizing psychopathology mediate the link between childhood ADHD and the subsequent development of SP by late adolescence. Aim 3 addresses another gap in the literature by examining how the persistence of ADHD subtype symptom dimensions through adolescence contributes to the development of SP using latent class/growth models. We hypothesize that persisting inattentive symptoms will be particularly important to the development of nicotine outcomes. The proposal thus addresses significant theoretical and practical questions regarding how ADHD confers risk for SP using sophisticated analytic approaches with a large, prospectively assessed, genetically informative community representative sample.